dimethylarginine and Proteinuria

Although the high risk for cardiovascular events in patients with end-stage renal disease (ESRD) is well known, recent data provide compelling evidence that even mild to moderate kidney disease is an important and independent risk factor for cardiac events. This increased risk does not seem to be explained by traditional risk factors as defined by the Framingham cohort. The examination of nontraditional risk factors has resulted in the identification of, among others, oxidant stress, hyperhomocystinemia, carbamylation, nitric oxide synthase inhibitors, and abnormal lipoproteins as potential pathways to explain the accelerated atherosclerosis in patients with kidney disease. Well-designed clinical trials should lead to the clarification of the relative importance of these factors in the pathogenesis of atherosclerotic disease.

Topics: Arginine; Cardiovascular Diseases; Humans; Hyperhomocysteinemia; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Lipoproteins; Lipoproteins, LDL; Nitric Oxide Synthase; Oxidative Stress; Proteinuria; Renal Dialysis; Risk Factors

Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease.. Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg⁻¹ day⁻¹), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation.. Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.

Topics: Animals; Arginine; Blood Pressure; Cardiomegaly; Disease Models, Animal; Hypertension, Renal; Kidney; Male; Nephrectomy; Nitrates; Nitric Oxide; Nitrogen; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary